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J Mol Cell Cardiol. 2015 Dec;89(Pt A):98-112. doi: 10.1016/j.yjmcc.2015.09.016. Epub 2015 Sep 28.

CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.

Author information

1
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland. Electronic address: samir.ounzain@chuv.ch.
2
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
3
Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
4
Centre for Heart Failure Research, Cardiovascular Research Institute, Maastricht University, The Netherlands.
5
Stem Cell and Developmental Biology Group, Genome Institute of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
6
Comparative Bioinformatics Group, Centre for Genomic Regulation, Barcelona, Spain.
7
Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain. Electronic address: rory.johnson@crg.es.
8
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland. Electronic address: thierry.pedrazzini@chuv.ch.

Abstract

Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis.

KEYWORDS:

Cardiac development; Cardiac precursor cells; Gene regulation; Heart failure; Long noncoding RNA; Super enhancer

PMID:
26423156
DOI:
10.1016/j.yjmcc.2015.09.016
[Indexed for MEDLINE]
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